N-arylations of aliphatic amines are important chemical transformations as the resulting aniline derivatives have found broad applications as pharmaceuticals, materials for organic electronics and dyes for industrial and research applications. Pyrazine and morpholine derivatives are of special interest, as these are found in a range of top selling pharmaceuticals.
A range of transition metal-catalyzed reactions has been developed for the formal halide to nitrogen substitution on aryl halides. Most renowned are the Ullmann and Buchwald-Hartwig couplings employing copper and palladium catalysis respectively. These results notwithstanding, the employment of transition metals as catalysts has several drawbacks in industrial applications, especially due to high costs, oxygen sensitivity, challenging purifications and toxic metal contaminants being present in the final products.
To overcome these shortcomings, catalyst-free SNAr reactions on highly activated halide-substituted benzene derivatives have been applied. However, the scope of this approach has so far been limited as strongly electron-withdrawing groups, such as nitro or cyano substituents, have been considered essential for reactivity. Thus, leading text books in organic chemistry describes: a) “Without electron-attracting groups present, nucleophilic aromatic substitution occurs only under extreme reaction conditions” F. A. Carey, R. J. Sundberg in Advanced Organic Chemistry: Part A: Structure and Mechanisms; 4th ed. Springer Science and Business Media, New York, 2000. b) “To summarize: Any anion-stabilizing (electron-withdrawing) group ortho or para to a potential leaving group can be used to make nucleophilic aromatic substitution possible.” J. Clayden, N. Greeves, S. Warren, P. Wothers in Organic Chemistry; Oxford University Press, New York, 2001.
WO 2014/191548 discloses a synthetic process for the production of 1-(2-((2,4-dimethyl-phenyl)sulfonyl)phenyl)piperazine by arylation in the presence of Cs2CO3. The process however requires incubation at elevated temperature for more than 14 days.